While metformin has been a first-line treatment for type 2 diabetes for over six decades, its precise mode of action remains not fully understood.
A collaborative research effort by scientists from Baylor College of Medicine and other international institutions has revealed an unrecognized role of the brain in mediating the therapeutic effects of metformin. By identifying a novel pathway in the brain involved in metformin's glucose-lowering action, researchers suggest new targets for more effective diabetes treatment options.
The findings are published in Science Advances.
Science Advances"The prevalent belief is that metformin decreases blood glucose primarily by lowering liver glucose production. Studies have also suggested its effects on the gut," stated Dr. Makoto Fukuda, associate professor of pediatrics—nutrition at Baylor and study's corresponding author.
"We explored the brain's involvement because it is pivotal in regulating whole-body glucose metabolism. We wanted to understand whether and how metformin acts via brain pathways."
The research team focused on a protein called Rap1, located within a specific brain region known as the ventromedial hypothalamus (VMH). Their results indicate that metformin's blood sugar-lowering ability at effective doses relies on inhibiting Rap1 in this specific area of the brain.
To ascertain these effects, Fukuda and his colleagues used genetically engineered mice lacking Rap1 in their VMH. These mice were fed a high-fat diet to simulate type 2 diabetes and were administered low metformin doses. Subsequently, metformin failed to reduce blood glucose levels, while other diabetes drugs like insulin and GLP-1 agonists remained effective.
To further demonstrate the brain's role, researchers micro-injected minimal doses of metformin directly into diabetic mice's brains. Blood sugar plummeted significantly despite using amounts thousands of times lower than oral doses.
"We additionally explored which cell types within the VMH mediated metformin's effects," Fukuda mentioned. "Our findings indicated that SF1 neurons become activated by metformin in the brain, confirming their involvement."
Using brain slices, scientists recorded these neurons' electrical activity. They observed increased neuron activity upon the introduction of metformin, but only when Rap1 was present. Conversely, metformin had no effect on mice lacking Rap1 in SF1 neurons.
"This discovery reshapes our understanding of how metformin functions," Fukuda stated. "It's not limited to liver or gut; it also acts through brain mechanisms. We found that the liver and intestines require high drug concentrations, but the brain responds to significantly lower levels.”
Although few anti-diabetic drugs target the brain directly, this study proves metformin does so. "These insights open avenues for developing new treatments targeting this specific brain pathway," Fukuda suggested.
"Moreover, considering metformin's recognized benefits such as slowing brain aging, we aim to research if Rap1 signaling in the brain is responsible for these additional effects."